ABSTRACT
This analysis assesses the factors underlying Charles Horton Cooley's place in the sociological canon as they relate to George Herbert Mead's puzzling diatribe-echoed in secondary accounts-against Cooley's social psychology and view of the self published scarcely a year after his death. The illocutionary act of publishing his critique stands as an effort to project the image of Mead's intellectual self and enhance his standing among sociologists within and outside the orbit of the University of Chicago. It expressed Mead's ambivalence toward his precursor Cooley, whose influence he never fully acknowledged. In addition, it typifies the contending fractal distinctions of the scientifically discursive versus literary styles of Mead and Cooley, who both founded the interpretive sociological tradition. The contrasting styles and attitudes toward writing of the two figures are discussed, and their implications for the problems of scale that have stymied the symbolic interactionist tradition are explored.
Subject(s)
Behaviorism/history , Psychology, Social/history , Sociology/history , Evaluation Studies as Topic , History, 20th Century , Humans , Knowledge , Psychological TheoryABSTRACT
Azetidinones such as BMS-363131 (2) and BMS-363130 (3), which contain a guanidine group in the C-3 side chain were previously shown to be very potent inhibitors of human tryptase with high selectivity versus other serine proteases, including trypsin. In this letter, we describe the discovery of a number of potent azetidinone tryptase inhibitors in which the guanidine moiety at the ring C-3 position is replaced with primary or secondary amine or aminopyridine functionality. In particular, BMS-354326 (4) is a highly potent tryptase inhibitor (IC(50)=1.8 nM), which has excellent selectivity against trypsin and most other related serine proteases.
Subject(s)
Azetidines/chemical synthesis , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Azetidines/chemistry , Azetidines/pharmacology , Humans , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , TryptasesABSTRACT
A series of N1-activated C4-carboxy azetidinones was prepared and tested as inhibitors of human tryptase. The key stereochemical and functional features required for potency, serine protease specificity and aqueous stability were determined. From these studies compound 2, BMS-262084, was identified as a potent and selective tryptase inhibitor which, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.
Subject(s)
Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/pharmacology , Azetidines/chemical synthesis , Azetidines/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Animals , Asthma/drug therapy , Asthma/pathology , Bronchoconstriction/drug effects , Crystallography, X-Ray , Extracellular Space/drug effects , Guinea Pigs , Half-Life , Humans , Inflammation/pathology , Lung/pathology , Molecular Conformation , Ovalbumin/immunology , Structure-Activity Relationship , TryptasesABSTRACT
The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are described, resulting in identification of BMS-363131 (2) as a potent inhibitor of human tryptase (IC(50)<1.7 nM) with high selectivity (>3000-fold) for tryptase versus related serine proteases including trypsin.
